5-Trifluoromethyluracil was originally synthesized in very low yield by a multistep procedure starting from trifluoroacetone cyanohydrin (Heidelberger, et al., J. Am. Chem. Soc., 84, 3597 (1962); J. Med. Chem., 7, 1 (1964)). Later, this compound was prepared more conveniently from uracil-5-carboxylic acid by treatment with sulfur tetrafluoride (Mertes, et al., J. Med. Chem., 9, 876 (1964)). The 2'-deoxynucleoside, i.e., 1-(2'-deoxy-.beta.-D-erythropentofuranosyl)-5-trifluoromethyluracil or F.sub.3 TDR, was prepared by condensation of the base and sugar halide in very low yield. (Heidelberger, et al., loc. cit). The trifluoromethyluracil nucleoside has shown activity against herpes simplex and many tumor systems (Heidelberger, Progr. Nucleic Acid Res. Mol. Biol., 4, 1 (1965); Cancer Res., 30, 1549 (1970)).
5-Difluoromethyluracil was also prepared but was found to be extremely labile in neutral aqueous media (Mertes, et al., loc. cit). No nucleoside containing this base has been synthesized. Attempts to synthesize 5-monofluorouracil have failed (Mertes, loc. cit). No 5-monofluoromethyluracil nucleoside is known.
Our theoretical considerations suggest that substitution of the N-1 position of 5-(partially-fluorinated)-methyluracils with an alkyl or sugar moiety should decrease the lability of the fluorine in the heterocyclic base. Therefore, nucleosides containing 5-(partially fluorinated) methyluracils should be obtainable by synthesis from a preformed nucleoside.